Bowman Caitlyn E, Wolfgang Michael J
Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Adv Biol Regul. 2019 Jan;71:34-40. doi: 10.1016/j.jbior.2018.09.002. Epub 2018 Sep 5.
Malonyl-CoA is a central metabolite in fatty acid biochemistry. It is the rate-determining intermediate in fatty acid synthesis but is also an allosteric inhibitor of the rate-setting step in mitochondrial long-chain fatty acid oxidation. While these canonical cytoplasmic roles of malonyl-CoA have been well described, malonyl-CoA can also be generated within the mitochondrial matrix by an alternative pathway: the ATP-dependent ligation of malonate to Coenzyme A by the malonyl-CoA synthetase ACSF3. Malonate, a competitive inhibitor of succinate dehydrogenase of the TCA cycle, is a potent inhibitor of mitochondrial respiration. A major role for ACSF3 is to provide a metabolic pathway for the clearance of malonate by the generation of malonyl-CoA, which can then be decarboxylated to acetyl-CoA by malonyl-CoA decarboxylase. Additionally, ACSF3-derived malonyl-CoA can be used to malonylate lysine residues on proteins within the matrix of mitochondria, possibly adding another regulatory layer to post-translational control of mitochondrial metabolism. The discovery of ACSF3-mediated generation of malonyl-CoA defines a new mitochondrial metabolic pathway and raises new questions about how the metabolic fates of this multifunctional metabolite intersect with mitochondrial metabolism.
丙二酰辅酶A是脂肪酸生物化学中的一种核心代谢物。它是脂肪酸合成中的限速中间体，但也是线粒体长链脂肪酸氧化限速步骤的变构抑制剂。虽然丙二酰辅酶A的这些典型细胞质作用已得到充分描述，但丙二酰辅酶A也可通过另一条途径在线粒体基质中生成：由丙二酰辅酶A合成酶ACSF3将丙二酸与辅酶A进行ATP依赖性连接。丙二酸是三羧酸循环中琥珀酸脱氢酶的竞争性抑制剂，是线粒体呼吸的有效抑制剂。ACSF3的一个主要作用是通过生成丙二酰辅酶A提供一条清除丙二酸的代谢途径，然后丙二酰辅酶A可被丙二酰辅酶A脱羧酶脱羧生成乙酰辅酶A。此外，ACSF3衍生的丙二酰辅酶A可用于使线粒体内基质中的蛋白质赖氨酸残基丙二酰化，这可能为线粒体代谢的翻译后调控增加另一层调节。ACSF3介导的丙二酰辅酶A生成的发现定义了一条新的线粒体代谢途径，并引发了关于这种多功能代谢物的代谢命运如何与线粒体代谢相互交叉的新问题。
